Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-16
2003-09-02
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S217060, C514S228200, C514S232500, C514S233800, C514S247000, C514S248000, C514S249000, C514S252020, C514S252110, C514S252170, C514S255050, C544S293000, C544S116000, C544S080000, C544S058600, C544S062000, C544S263000, C544S264000, C544S235000, C544S257000, C540S600000
Reexamination Certificate
active
06613772
ABSTRACT:
This is a 371 of PCT/EP98/08097, filed Dec. 11, 1998.
The present invention relates to compounds of the formula I
which are suitable for the production of pharmaceuticals, for example for the prophylaxis and therapy of cardiovascular conditions such as high blood pressure, angina pectoris, cardiac insufficiency, thromboses or atherosclerosis. The compounds of the formula I have the ability to modulate the endogenous production of cyclic guanosine monophosphate (cGMP) and are generally suitable for the therapy and prophylaxis of disease states which are associated with a disturbed cGMP balance.
Cyclic guanosine monosphosphate (cGMP) is an important intracellular messenger which, via the modulation of cGMP-dependent protein kinases, phosphodiesterases and ion channels, induces a large number of various effects. Examples are smooth muscle relaxation, the inhibition of platelet activation and the inhibition of smooth muscle cell proliferation and leukocyte adhesion. cGMP is produced by particulate and soluble guanylate cyclases as a response to a number of extra- and intracellular stimuli. In the case of the particulate guanylate cyclases, the stimulation essentially takes place by means of peptide signal substances, such as the atrial peptide or the cerebral natriuretic peptide. The soluble guanylate cyclases (sGC), which are cytosolic, heterodimeric heme proteins, however, are essentially regulated by a family of low molecular weight, enzymatically formed factors. The most important stimulant is nitrogen monoxide (NO) or a closely related species; the importance of other factors such as carbon monoxide or the hydroxyl radical is still largely unexplained. The binding of NO to the heme with formation of a pentacoordinated heme-nitrosyl complex is discussed as an activation mechanism. The release associated therewith of the histidine bound in the basal state to the iron converts the enzyme into the activated conformation. Active soluble guanylate cyclases are composed of one &agr;- and one &bgr;-subunit each. A number of types of subunits are described, which differ from one another with respect to sequence, tissue-specific distribution and expression in various stages of development. The subtypes &agr;
1
and &bgr;
1
are mainly expressed in the brain and lung, while &bgr;
2
is mainly found in the liver and kidney. It was possible to detect the sub type &agr;
2
in human fetal brain; the subunits designated as &agr;
3
and &bgr;
3
were isolated from human brain and are homologous to &agr;
1
and &bgr;
1
. More recent work indicates an &agr;
2
subunit, which contains an insert in the catalytic domain. All subunits exhibit great homology in the area of the catalytic domain. The enzymes presumably contain one heme per heterodimer, which is bonded via &bgr;
1
-Cys-78 and/or &bgr;
1
-His-105 and is part of the regulatory center.
Under pathological conditions, the formation of guanylate cyclase-activating factors can be decreased, or intensified degradation thereof can take place due to the increased occurrence of free radicals. The decreased activation of the sGC resulting from this leads via the reduction -of the respective cGMP-mediated cell response to a rise in the blood pressure, to platelet activation and to increased cell proliferation and cell adhesion. As a result, the development of endothelial dysfunction, atherosclerosis, high blood pressure, stable and unstable angina pectoris, thromboses, myocardial infarct, strokes or erectile dysfunction occurs.
The pharmacological stimulation of the sGC offers one possibility for the normalization of the cGMP production and thus allows the treatment or prevention of these diseases. For the pharmacological stimulation of the sGC, until now compounds such as, for example, nitrates were exclusively used, whose action is based on an intermediate release of NO. The disadvantage of this method of treatment lies in the development of tolerance and the higher dose which is therefore necessary.
Various quinazolines and pharmacological actions of quinazolines are already known. 2-(p-chlorophenyl)-4-(1-diethylamino-4-pentylamino)-6,7-dimethoxyquinazoline dihydrochloride has been published without indication of the potency in connection with compounds which have an antimalaria action (R. L. McKee, M. K. McKee and R. W. Bost, J. Amer. Chem. Soc. 68: 1902-1903 (1946)).
2-Alkylquinazolines have been described as bronchodilating and hypotensive compounds (U.S. Pat. No. 3,594,480). Specific 2-phenylquinazolines which contain nitrato groups in the 4-amino substituents have been described as antianginal agents (DE-A-2 338 669). 2-Arylquinazolines which contain phosphonato groups have additionally been described as agents for the treatment of hyperlipidemia, hypertension and diabetes (EP-A-0 655 456).
In the attempt to find efficacious compounds for the modulation of the endogenous production of cyclic guanosine monophosphate (cGMP), which are suitable for the therapy and prophylaxis of disease states which are associated with a disturbed cGMP balance, it has now been found that the quinazolines of the formula I bring about a strong activation of guanylate cyclase and are thus suitable for the treatment of diseases which are associated with a low cGMP level.
The present invention therefore relates to compounds of the formula I
and/or stereoisomeric forms of the compounds of the formula I and/or mixtures of such forms in all ratios and/or physiologically tolerable salts of the compounds of the formula I, in which
R
1
and R
2
are identical or different and independently of one another are
1. hydrogen,
2. (C
1
-C
5
)-alkyl,
3. (C
1
-C
5
)-alkyl, which is mono-, di- or trisubstituted by
3.1 —OH
3.2 —O—(C
1
-C
6
)-alkyl,
3.3 —SH,
3.4 —SR
4
, in which R
4
is (C
1
-C
6
)-alkyl,
3.5 —N(R
6
)R
7
, in which R
6
and R
7
are identical or different and independently of one another are hydrogen or (C
1
-C
6
)-alkyl,
3.6 —C(O)—N(R
6
)R
7
, in which R
6
and R
7
are identical or different and independently of one another are hydrogen or (C
1
-C
6
)-alkyl, or R
6
and R
7
, together with the N atom to which they are bonded, form a morpholine, piperazine, imidazole, piperidine, pyrrolidine, thiomorpholine, 1-oxothiomorpholine, 1,1-dioxothiomorpholine or hexamethyleneimine radical,
3.7 —O—(C
1
-C
6
)-alkyl, which is mono-, di- or trisubstituted by
3.7.1 —OH,
3.7.2 —SH,
3.7.3 ═O,
3.7.4 —COOH,
3.8 —COOH,
3.9 —C(O)—O—R
8
, in which R
8
is (C
1
-C
6
)-alkyl,
3.10 phenyl,
3.11 phenyl, which is mono-, di- or trisubstituted by
3.11.1 —O—(C
1
-C
4
)-alkyl,
3.11.2 —O-phenyl,
3.11.3 (C
1
-C
4
)-alkyl,
3.11.4 —NO
2
,
3.11.5 halogen,
3.11.6 —C(R
9
)(R
10
)R
11
, in which R
9
, R
10
and R
11
independently of one another are hydrogen or halogen,
3.12 a radical of a heterocycle from the group consisting of morpholine, piperazine, imidazole, piperidine, pyrrolidine, pyridine, thiomorpholine, 1-oxothiomorpholine, 1,1-dioxothiomorpholine, hexamethyleneimine, pyrrole, pyrazole, pyridazine, pyrazine, pyrimidine, indolizine, indole, indazole, purine, quinoxaline, furan, quinazoline, cinnoline, pteridine, oxazole, isoxazole, thiazole, isothiazole, furazan, indoline, pyrazoline, thiophene, xanthine, imidazoline and pyran,
3.13 a radical of a heterocycle described in 3.12, which is mono-, di-, tri- or tetrasubstituted by
3.13.1 (C
1
-C
4
)-alkyl,
3.13.2 ═O,
3.13.3 halogen,
3.13.4 —O—(C
1
-C
4
)-alkyl,
3.13.5 —NO
2
,
4. (C
3
-C
7
)-cycloalkyl, which is unsubstituted or substituted by
4.1 (C
1
-C
4
)-alkyl,
4.2 —OH,
4.3 —O—(C
1
-C
4
)-alkyl,
4.4 —NH
2
,
5. a radical of a heterocycle from the group consisting of morpholine, piperazine, imidazole, piperidine, pyrrolidine, pyridine, thiomorpholine, 1-oxothiomorpholine, purine, 1,1-dioxothiomorpholine, hexamethyleneimine, pyrrole, pyrazole, pyrazine, pyrimidine, pyridazine, indolizine, indole, indazole, quinoxaline, quinazoline, cinnoline, pteridine, oxazole, isoxazole, thiazole, isothiazole, furan, furazan, indoline, pyrazoline, thiophene, xanthine, imidazoline and pyran, where this heterocycle is unsubstituted or substituted
Schindler Peter
Schindler Ursula
Schönafinger Karl
Strobel Hartmut
Aventis Pharma Deutschland GmbH
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Ford John M.
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